Cyclobutanones reduction

This chapter begins by classifying the combinations of oxidation/reduction processes with subsequent cationic transformations, though to date the details of only two examples have been published. The first example comprises an asymmetric epoxidation/ring expansion domino process of aryl-substituted cyclopropyl-idenes (e. g., 7-1) to provide chiral cyclobutanones 7-3 via 7-2, which was first described by Fukumoto and coworkers (Scheme 7.1) [2]. 

A nickel(O) complex catalyzes insertion of alkynes into cyclobutanones (Equation (79)).437 Formation of metalla-cycle 194 via oxidative cyclization of an alkyne with the carbonyl group of a cyclobutanone followed by /3-carbon elimination (formation of metallacycle 195) and reductive elimination are postulated for the mechanism (Scheme 92). 

Consequently, haloketenes can be readily generated in situ by two most widely used methods (a) the triethylamine dehydrohalogenation of an acyl halide (Eq. (3))50) (b) the dehalogenation of an a-haloacyl halide with activated zin (Eq. (4))51). Since the halogen substituents on the cyclobutanone can be reductively removed by usual procedures, the synthesis of a halocyclobutanone constitutes a formal preparation of the cyclobutanone, the synthetic utility of which is convincingly demonstrated by the following examples. 

The cyclobutanone (255) reacted with acid to furnish the keto-acid (259). Upon esterification, ketalization and reduction, (259) was converted to the alcohol (260). Mesylation of the alcohol (260) and then treatment of the mesylate with NaN3 in DMSO provided the azide (261). The azide (261) was then transformed to the urethane (262) by reduction and ethyl chloroformate reaction. The urethane (262) was deketalized by acid, nitrosated by N204—NaOAc and decomposed by NaOEt—EtOH to give the ketone (263) 89). The ketone (263) served as a starting material for the synthesis of veatchine (264)90). 

In work which remains unpublished, Wenkert has succeeded in cleverly transforming 2-methylcyclopentanone into isocomene The key elements of his strategy (Scheme LXXXIII) are the acid-catalyzed ring expansion of methoxycyclopropane 747 to 748 and the regiospecific homologation of the cyclobutanone to 749. Unfortunately, the Wolff-Kishner reduction of this penultimate intermediate affords both 731 and its epimer. 

Derivatives other than cyclobutanones can be obtained from the ketene iminium salt by way of reduction with hydride ion of the cyclobutaneiminium salt to give cyclobutylamines. Although some stereoselectivity is observed, mixtures of stereoisomers are usually obtained, e.g. formation of 12.13... 

Like their sulfur counterparts (Section 3.2.4.4.2.), 1 -lithiocyclopropyl selenides 1, as generated by reductive lithiation of bis(selanyl)cyclopropanes 173 with butyllithium in diethyl ether or tetrahydrofuran, react with aldehydes or ketones to give /Lhydroxy selenides 2, which rearrange to cyclobutanones 3 on treatment with p-toluenesulfonic acid in wet benzene.174 175 The method was used in a total synthesis of a-cuparenone.175... 

Chiral 2,2-disubstituted cyclobutanones have been obtained by asymmetric rearrangement of chiral sulfinyl- 177,178 and sulfanylcyclopropanes.179 Using readily available cyclopropyl 4-tolyl (/ )-sulfoxide (l),180 the requisite sulfinylcyclopropanes 3 and 3 were obtained by a sequence of lithiation, reaction with carboxylic acid esters and stereoselective addition of Grignard reagents to the ketones 2 thus formed.178 The corresponding sulfanylcyclopropanes 4 and 4 resulted from a sequence of protection, reduction and deprotection.179... 

Other methods have appeared, but have been less frequently used, e.g. chromium chloride in acetone 140- 143 (y/yfe infra) and dissolving alkali-metal reductions.144,145 Hydrogenolysis with palladium/hydrogen has also given the monoreduced cyclobutanone.99,100... 

A common alternative to the Wolff-Kishner reduction of cyclobutanones to the parent cyclobutane (see Section S.2.4.2.), is formation of thiocetals (see Section 5.2.4.7.1.) followed by hydrogenolyses using Raney nickel.64,146-149 For example, l,4,4-trimethyl-6,6-(propane-l,3-diyldithia)bicyclo[3.2.0]heptan-3-one gave 15 using this method. It was found that the W-2 quality of Raney nickel works well.64"148... 

Functional Group Interconversions Including Functionalization 5.2.4.1, Formation of One C—H Bond Reduction of Cyclobutanone to Cyclobutanol... 

Since cyclobutanones are often produced by dichloroketene addition to an alkene (see Section 1.3.5.1.), a,a-dichlorocyclobutanones are very common intermediates. These can be reduced to the monochlorocyclobutanones (see Section 5.2.1.1.). It was reported249 that the C —Cl dipole has a pronounced effect on the sodium borohydride reduction of these compounds. For example, in the reduction of e ra-7-chloro-7-methylbicyclo[3.2.0]hept-2-en-6-one, the normal preference for an exo-face attack was reversed and the exo-alcohol was the major product exo-7-chlorobicyclo[3.2.0]hept-2-en-exo-6-ol exo-2d and exo-7-chlorobicy-clo[3.2.0]hept-2-en-en /o-6-ol endo-2A were obtained in a 78 22 ratio. On the other hand, when the corresponding endo-chloro ketones were reduced, the C —Cl dipole resulted in exclusive formation of the endo-alcohols endo-2b, c. 

Reduction of a cyclobutanone with baker s yeast yielded the diastereomeric alcohols 5 which could be separated by column chromatography.163 The optical purity was reported to be ca. 90%. Stereoselective reductions using isolated enzymes or complete organisms have also been reported for 6.82-276 278... 

Modified Wolff-Kishner methods work well on ordinary cyclobutanones. Generally, the hydrazones are made at fairly mild reaction temperatures, base is added and the cyclobutane is distilled directly from the hot reaction mixture.237,272 279-284 The hydrazone can also be isolated prior to the reduction.285 The relatively facile reduction of cyclobutanones which occurs before that of larger ring ketones can be utilized in the selective reduction of cyclobutanones in the presence of, for example, a cyclohexanone, i.e. pentaspiro[3.1.3.3.3.3]heneicosane-5,11,19-trione was reduced in a stepwise manner to pentaspiro[3.1.3.3.3.3]heneicosane-5-one.237... 

Further examples of the modified Wolff-Kishner reduction of cyclobutanones to cyclobutanes are given in Table 13. 

Bromoallyl)cyclobutanones rearranged to give bicyclo[4.1.0]heptan-3-ones 7 and 8 on reduction with tributyltin hydride.119... 

In recent years, inorganic hydrides such as lithium aluminum hydride, LiAlH4, and sodium borohydride, NaBH4, have become extremely important as reducing agents of carbonyl compounds. These reagents have considerable utility, especially with sensitive and expensive carbonyl compounds. The reduction of cyclobutanone to cyclobutanol is a good example, and you will... 

Pressure reductions have been observed for methane hydrate formation when organic components (that are very insoluble in water) are added to the water + methane system. These organic components include THP, cyclobutanone, methylcyclohexane, CHF3, and CF4 (Mooijer-van den Heuvel et al., 2000 ... 

Hara et al., 2005). THP, cyclobutanone, and cyclohexane also showed pressure reductions for carbon dioxide hydrate formation (Mooijer-van den Heuvel et al., 2001). THP, cyclobutanone, cyclohexane, and methylcyclohexane all reduced not only the pressure for propane hydrate formation, but also shifted the H-Lw-Lc3H8 line to lower temperature (Mooijer-van den Heuvel et al., 2002). 

The (2 + 2) cycloaddition reactions of ketenes with alkenes are synthetically useful routes to cyclobutanones. Ketenes are particularly useful due to the low steric hindrance at the carbonyl carbon. An example is the reaction of dichloro-ketene with cyclopentadiene which, after reductive dechlorination of the product, gives bicyclo[3.2.0]hept-2-en-6-one (Expt 7.25). 

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